Substituted aroylalkyl phenothiazinylalkyl piperazines



Unite mtes 3,000,886 SUBSTITUTED AROYLALKYL PHENOTHIAZINYL- ALKYLPIPERAZINES William H. Edgerton, Stralford-Wayne, Maxwell Gordon,

Philadelphia, and James W. Wilson, Wayne, Pa., assignors to Smith Kline& French Laboratories, Philadelphia, Pa., a corporation of PennsylvaniaNo Drawing. Filed Oct. 6, 1958, Ser. No. 765,295 2 Claims. (Cl. 2'60243)This invention relates to novel substituted l-aroylalkyl- 4-(10-phenothiazinylalkyl)-piperazines which have a broad spectrum ofutility as therapeutic agents in various animal organisms. Morespecifically, the compounds of this invention have utility astranquilizers, antiemetics, sedatives, antihistaminics, anticonvulsantsand potentiators of various central nervous system depressants, such asanalgetics or anesthetics. Of particular importance are thetranquilizing and antiemetic activities of these compounds, especiallythe former activity which makes them suitable for the treatment ofmental illness.

In addition, these compounds have chemotherapeutic or antimicrobialactivity, such as antileprosy, antitubercular, antibacterial andanti-fiungal activity. For example, they possess antifungal orantibacterial activity, such as against Diplococcus pneumoniae Type I,Hemolytic streptococcus, Micrococcus pyogenes var. aureus, Klebsiellapnuemoniae and Candida albicans. Those compounds containing atn'fluoromethyl moiety are particularly advantageous. Further, thesecompounds have anthelmintic activity, such as against the St-rongylinaesubfamily.

The substituted l-aroylalkyl-4-(l0-phenothiazinylalkyl)-piperazines ofthis invention are represented by the following general formula:

Formula 1 AN N-(CHzh-Pl-Ri Ra when:

Y represents hydrogen, chlorine, trifluoromethyl, methyl, methoxy,acetyl, methylmercapto, t-rifluoro- Formula 2 S (ll) asasss PatentedSept. 19, 196i when:

Y represents chlorine, tn'fluoromethyl, methylmercapto,trifiuoromethylmercapto, trifiuoromethylsulfonyl, or cyano;

A represents a divalent, straight or branched alkylene chain containingfrom 2 to 4 carbon atoms, separating the two nitrogens to which it isattached by at least two carbon atoms;

n represents a positive integer of from 1 to 3; and

R represents phenyl, p-methoxyphenyl or p-tolyl.

Preferred compounds of this invention are represented by Formula 2 when:

Y represents trifluoromethyl;

A represents a divalent, straight or branched alkylene chain containingfrom 2 to 4 carbon atoms, separating the two nitrogens to which it isattached by at least two carbon atoms;

n represents a positive integer of from 1 to 3; and

R represents phenyl.

A particularly preferred and advantageous compound is l-(2-benzoylethyl)-4- [3- Z-trifluoromethyll 0-phenothiazinyl -propyl] -pip erazine.

This invention also includes acid addition salts of the above definedbases formed with nontoxic pharmaceutically acceptable organic andinorganic acids. Such salts are easily prepared by methods known to theart. The base is reacted with either the calculated amount of organic orinorganic acid in aqueous miscible solvent, such as acetone or ethanol,with isolation of the salt by concentration and cooling or an excess ofthe acid in aqueous immiscible solvent, such as ethyl ether orchloroform, with the desired salt separating directly. Exemplary of suchorganic salts are those with maleic, fumaric, benzoic, ascorbic,parnoic, succinic, bismet'hylenesalicylic, .methanesulfonic,ethanedisu-lfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids as well as with theS-halotheophyllines, for example, 8-bromo-theophylline. Examples of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids. Of course these salts may also beprepared by the classical method of double decomposition of appropriatesalts which is well-known to the art.

The novel substitutedl-aroylalkyl-4-(IO-phenothiazinylalkyl)-piperazines of this inventionare prepared according to the following synthetic scheme:

Clio} l tmi when X represents chlorine, bromine or iodine; Y, A, R R Rand n are as defined above; and R represents benzyl, formyl,carbobenzoxy, carbomethoxy or carbethoxy.

The substituted phenothiazine starting materials are prepared followingknown methods. Thus, a substituted 2-halo-2'-aminodiphenyl sulfide iscyclized in the presence of an acid-binding agent, for example sodium orpotassium carbonate, and catalytic amounts of copper or copper bronzepowder, by refluxing in dimethylformamide for from 6 to 19 hours.

Alternatively, the substituted phenothiazines are prepared fromdiphenylamines. In this method, appropriately substituted diphenylaminesare heated with sulfur in the presence of a catalytic amount of iodinewith or without a solvent at from 120 to 230 C. for from one to fourhours.

As outlined above, the substituted phenothiazines are alkylated with anw-haloalkylpiperazine having the free N-hydrogen of the piperazinylmoiety replaced by an easily removed moiety, R, as defined above. R ispreferably carbethoxy. The al-kylation is achieved advantageously byrefluxing an w-haloalkylpiperazine, preferably chloro or bromo, and asubstituted phenothiazine in a suitable inert aromatic solvent such as,preferably, benzene, toluene or xylene, in which atleast one of thereactants must be soluble. A suitable acid-binding agent is usuallyincluded, such as an alkali metal amide, preferably sodium, potassium orlithium amide. The reaction mixture is refluxed for from 3 to 18 hoursand worked up after cooling by adding an excess of water, extractingwith dilute hydrochloric acid, neutralizing with base and extractingwith benzene. Evaporation of the benzene extracts yields the residualbase. The N- protective group, R is then removed under mild conditions,such as by alkaline hydrolysis with for example sodium hydroxidesolution in the case of the preferred carbet-hoxy group, to yield thesubstituted l-piperazinylalkyl phenothiazines.

Another synthetic route to the l0-piperazinylalkyl phenothiazines is bymeans of lO-(w-ester-alkyl)-phenothiazines which have a reactive endgroup on the 10- alkyl chain, for example an w-tosylate or w-ChlOl'O endgroups, which can be reacted with a piperazine having one N-hydrogenreplaced by R, as described above. For example, the ester and piperazineare refluxed in the presence of an acid-binder for a short period andfurther worked up as described above.

The substituted lO-piperazinylalkyl phenothiazine is then furtherreacted to prepare the compounds of this invention. Thus, thephenothiazine is reacted with an aroylalkyl halide of the formula,

where X represents chlorine, bromine, or iodine, and n and R are asdefined above. The reaction is carried out advantageously in a suitableinert organic solvent such as, preferably, a lower-carbon amide, forexample dimethylformamide, by heating the reactants at from about 50450C. for from 30 minutes to 12 hours, preferably 1 to 8 hours.Alternatively, an acid-binding agent such as sodium or potassiumcarbonate is employed. The substituted 1-aroylalkyl-4-(10phenothiazinylalkyl) piperazine is isolated by coolingthe reactionmixture and pouring it into an excess of water. The mixture is madealkaline with dilute sodium hydroxide solution and extracted withchloroform. The dried chloroform extracts are evaporated to yield aresidue which rnay be an oily base or a crystalline solid. The oily baseis often purified by fractional distillation under high vacuum; thecrystalline solid is purified by recrystallization. In practice thebasic oil or solid is dissolved in an organic solvent and converted to astable acid addition salt by reaction with a suitable organic orinorganic acid as described hereinbefore.

'An alternative and advantageous method for the preparation of1-aroylethyl-4-(lO-phenothiazinylalkyl)-piperazines (n representing 2.in Formula 1 above) employs the general reaction conditions of theMaunich reaction, namely the condensation of a carbonyl compound withformaldehyde and a secondary amine. Thus, a solution of an acetophenoneof the formula,

where R is as defined above, paraformaldehyde and a substitutedlfl-piperazinylalkyl phenothiazine in a lower carbon alcohol such asethanol is heated at reflux for from 3 to 6 hours in the presence ofconcentrated hydrochloric acid. Concentrating the cooled, filteredreaction mixture yields the dihydroc-hloride salt. The free base isisolated optionally by neutralizing an aqueous solution of thedihydrochloride salt, extracting with benzene or chloroform andevaporating the extracts to dryness in vacuo. The residual free base ispurified or converted to another acid addition salt by methods describedhereinbefore.

The foregoing is a general description of the main synthetic routes inthe preparation of substituted 1-aroy1alkyl-4-(10-phenothiazinylalkyl)-piperazines. It will be readilyapparent to one skilled in the art that variations of these proceduresare possible. Of particular advantage as preparative procedures are themethods thoroughly discussed above, namely, alkylation of substituted10-piperazinylalkyl phenothiazines with an aroylalkyl halide or with anacetophenone and formaldehyde, and alkylation of substitutedphenothiazines in the 10- position of the nucleus with anw-haloalkylpiperazine having the free N-hydrogen of the piperazinemoiety replaced by an easily removed group.

It Will be readily apparent to one skilled in the art that certain ofthe compounds of this invention, notably those in which A is representedby an aliphatic carbon chain branched so that an asymmetric carbon atomis formed may be present as optical isomers. The connotation of thegeneral formulae presented herein is to include all isomers,particularly the separated d or 1 optical isomers as well as the dlmixture of these isomers. If desired, the isomers may be separated forindividual use by separation methods known to the art, such asfractional crystallization, for instance, of the d-tartrate salts of thesubstituted 1-aroylalkyl-4-( 10-phenothiazinylalkyl)-piperazinederivatives. Alternatively, a synthesis starting, with an opticallyactive side chain may yield the desired optical isomer.

The following examples are not limiting but are illustrative ofcompounds of this invention and the procedures for their preparation andwill serve to make fully apparent all of the compounds embraced by thegeneral formula given above and the preparation thereof respectively.

Example 1 A suspension of 13.4 g. of 2'-trifluoromethylphenothiazine and2.0 g. of sodium amide in 175 ml. of toluene r is refluxed withrapidstirring for 15' minutes. A solution l bromo-3-chloropropane) in 75ml. of toluene is added and refluxing continued for six hours. Thecooled reaction mixture is treated with 100 m1. of water and the toluenelayer is extracted with dilute hydrochloric acid. The acid extracts aremade basic with ammonia and then extracted with benzene. The benzene isremoved by distillation in vacuo to yield the residual10-[3-(N-carbethoxypiperazinyl) propyl] 2 trifluoromethylphenothiazrne.

A solution of 7.0 g. ofl-[3-(N-carbethoxypiperazinyl)-propyl]-2-trifluoromethylphenothiazine in25 ml. of ethanol and 20 ml. of water containing 2 ml. of 40% sodiumhydroxide solution is heated at reflux for two hours. The ethanol isdistilled oil in vacuo on the steam bath. The residue is treated withbenzene-water and the dried organic layer evaporated in vacuo to give-(3- pip erazinylpropyl) -2-trifluoromethylphenothiazine.

A solution of 13.0 g. of l0-(3-piperazinylpropyl)-2-trifluoromethylphenothiazine, 3.3 g. 'of acetophenone, 1.3 g. ofparaformaldehyde, and 0.8 ml. of concentrated hydrochloric acid in 25ml. of ethanol is stirred at reflux for one hour. An additional 0.9 g.of paraformaldehyde is added and refluxing is continued for three hours.The solid which forms is filtered and the filtrate concentrated. Uponthe addition of 50 ml. of acetone and cooling, a pale yellow solid formswhich is removed by filtration. This solid is recrystallized fromethanol to give pale yellow crystals of1-(2-benzoylethyl)-4-[3-(2-trifluoromethyl 10 phenothiaziny-l)-propyl1-piperazine dihydrochloride, M.P. 191193 C.

Example 2 A mixture of 10.0 g. of phenothiazine, 2.1 g. of sodam ide and13.6 g. of N-carbethoxy-N-(3-chloropropyl)- Z-methylpiperazine (preparedby reacting the N-carbethoxy derivative of 2-metl1ylpiperazine with1-bromo-3- chloropropane) in 200 ml. of toluene is heated at reflux withstirring for eight hours. The cooled reaction mixture is worked up as inExample 1 to give 10-[3-(N- carbethoxy-Z-methylpiperazinyl) -propyl]-phenothiazine.

A solution of 4.1 g. of the above phenothiazine derivative in 25 ml. ofethanol and ml. of water containing 1 ml. of 40% sodium hydroxidesolution is refluxed for two hours. The solvent is removed and thereaction mixture further treated as described in Example 1 to yield l0-3-(2-methylpiperazinyl) -propyl] -phenothiazine.

A solution of 4.0 g. of a-chloro-p-methoxyacetophenone and 6.8 g. of10-[3-(2-methylpiperazinyl)-propyl]- phenothiazine in 100 ml. ofdimethylformarnide is stirred and heated at 80 C. for four hours. Thecooled reaction mixture is poured into water, made alkaline with 10%sodium hydroxide solution and extracted with chloroform. The driedchloroform extract is evaporated in vac-no to yieldl-(p-methoxybenzoylmethyl)-4-[3-(10- phenothiazinyl) -propyl]-2-methylpiperazine.

Example 3 A mixture of 11.6 g. of 2-chlorophenothiazine, 1.2 g. oflithium amide and 13.6 g. of N-carbethoxy-N'-(3chloro-Z-methylpropyl)-piperazine (prepared from the reaction ofN-carbethoxypiperazine and 1-bromo-3- chloro-Z-methylpropane) in 250 ml.of toluene is refluxed for eight hours and then worked up as in Example1 to yield 10- 3- (N-carbethoxypiperazinyl) -2-methylprop/yl]Z-chlorophenothiazine.

An ethanolic solution of 13.3 g. of the above-prepared plrenothiazinewith 30 ml. of water containing 3 ml. of 40% sodium hydroxide solutionis refluxed for two hours. Removal of the solvent and treating thereaction mixture as described in Example 1 furnishes 2-ohloro-10-(2-methyl-3-piperazinylpropyl) -phenothiazine.

A solution of 3.7 g. of2-chiorol0-(2-methyl-3-piperazinylpropyl)-phenothiazine and 2.4 g. ofB-bromopropiophenone in 75 ml. of dimethylformamide is heated at 100 C.for eight hours. Upon working up the reaction mixture as in Example 2,1-(2-bi1.Z.9ylethy1)-4-L3-(2- chloro-lO-phenothiazinyl) -2-methylpropyl]-piperazine is isolated.

Treating the free base with an ethyl acetate solution of bismethyle'nesalicylic acid yields the bismethylene salicylate salt.

Example 4 A solution containing 11.3 g. of 10-(2-piperazinylethyl)-Z-trifiuoromethylphenothiazine and 6.5 g. ofp-chloro-pmethoxypropiophenone in 150 ml. of dimethylformamide isstirred andheated at C. for eight hours. The cooled reaction mixture istreated with water and made alkaline with dilute sodium hydroxidesolution. The alkaline solution is extracted with chloroform and theextracts washed with Water. The combined dried extract is evaporated invacuo to yieldl-(p-methoxybenzoylethyl)-4-[2-(Z-trifluoromethyl-10-phenothiazinyl)ethyl]- piperazine.

The base is reacted with anhydrous hydrogen bromide gas in an ethersolution to give the dihydrobromide salt.

Example 5 A suspension of 7.5 g. of Z-methylphenothiazine, 1.4 g. ofsodamide and 7.3 g. of N-formyl-N'-(3-chloropropyD-piperazine in 175 ml.of toluene is stirred and heated at reflux for eight hours. Water isadded to the cooled reaction mixture, the organic layer separated andthen extracted with dilute mineral acid. The acid extracts are madebasic with ammonia and extracted with benzene. Removal of the solventyields 10-[3-(N-formylpiperazinyl)-propyl]-2-methylphenothiazine. Theformyl group is hydrolyzed in aqueous ethanol with 40% sodium hydroxidesolution as outlined in Example 1.

A solution of 6.8 g. of 2-methyl-10-(3-piperazinylpropyD-phenothiazine(obtained from above) and 4.3 g. of -ohloro-p-methylbutyrophenone in 150ml. of dimethylformamide is stirred and heated at C. for eight hours.The cooled reaction mixture is treated as described in Example 2 toyieldl-(p-methylbenzoylpropyl)-4-[3-(2-methyl-l0-phenothiazinyl)-propyl]piperazine.

Example 6 A solution of 11.5 g. of Z-methoxyphenothiazine in 250 ml. oftoluene is alkylated with 12.5 g. of N-carbethoxy- Example 7 A mixtureof 3.1 g. of 2-acetyl-10-(3-chloropropyl)- phenothiazine, 0.4 g. ofsodium amide and 1.8 g. of N- carbethoxypiperazine in 150 m1. of tolueneis stirred and refluxed for eight hours. The cooled reaction mixture isworked up as in Example 1 to yield2-acetyl-l0[3-(N-carbethoxypiperazinyl) -propyl]-phenothiazine.

A solution of 13.1 g. of2-acetyl-IO-[B-(N-carbethoxypiperazinyl)-propyl]-phenothiazine in 50 ml.of ethanol and 30 ml. of water containing 3 ml. of 40% sodium hydroxidesolution is refluxed for two hours. Working up the reaction mixture asin Example 1 yields 2-acetyl-10- (3piperazinylpropyl)-phenothiazine.

A solution of 7.3 g. of'Z-acetyl-l0-(3apiperazrinylpropyl)-phenothiazineand 4.7 g. of oc-bromo-p-methylacetophenone in ml. of dimethylformamideis heated at 80 (.3. with stirring or tour hours. The coolest solution 7is worked up as in Example 2 to yield 1-p-methylbenzoylmethyl)-4-[3-(2-acetyl-IO-phenothiazinyl)propyl]-piperazme.

The free base is treated with ethereal hydrogen chloride to give thedihydrochloride salt.

Example 8 A suspension of 9.8 g. of Z-methylmercaptophenothiazine and1.6 g. of sodium amide in 150 ml. of toluene is refluxed and stirred for30 minutes. A solution of 10.4 g. ofN-carbethoxy-N-(2-chloropropyl)-piperazin-e in 150 ml. of toluene isadded and refluxing continued for eight hours. The cooled reactionmixture is treated as in Example 1 to yield-[Z-(N-carbethoxypiperazinyl)-isopropyl]-2-rnethylmercaptophenothiazine. A solution of the phenothiazinein aqueous ethanol in the presence of 40% sodium hydroxide solution isrefluxed for two hours to give the hydrolysis product,2-methylmercapto-l0-(2- pip erazinylis opropyl -ph enothiazine.

A solution of 2.5 g. of 'y-bromo-butyrophenone and 3.7 g. ofZ-methylmercapto-IO-(Z-piperazinylisopropyl)-phenothiazine in 75 ml. ofdirnethylformann'de is stirred and heated at 130 C. for eight hours.Working up as outlined in Example 2 yields 1-(3-benzoylpropyl)4-[2-(2-methylmercapto lO-phenothiazinyl)isopropyl] piperazine.

By reacting the free base dissolved in acetone with an acetone solutionof citric acid, the dicitrate salt is formed.

Example 9 To a solution of 284.5 g. of 3-bromopl1enyl methyl sulfide in1425 ml. of dry chloroform at 10 0., dry chlorine is introduced whilethe solution is irradiated with a 150 watt lamp. The reaction mixture ismaintained at -18 C. for six and one-half hours. The reaction 1s stoppedand a vigorous stream of nitrogen is introduced. The'solvent is removedunder pressure and the residue distilled to give a yellow oil,3-bromophenyl trichloromethyl sulfide, B.P. 102-104 C./ 1.1 mm.

A mixture of 142.0 g. of 3-bromophenyl trichloromethyl sulfide and 110.0g. of antimony trifluoride is heated in a distillation flask and thefraction boiling at 190-205 C. is collected. This fraction is dissolvedin 800 ml. of ether and washed several times with 6 N hydrochloric acidand then water. The ether solution is dried and the solvent removedunder reduced pressure. Distillation at atmospheric pressure yields acolorless lliquid, 3-bromophenyl trifluoromethyl sulfide, B.P. 192- Amixture of 160.0 g. of 3-br0mophenyl trifluoromethyl sulfide, 100.0 g.of acetanilide, 52.9 g. of anhydrous potassium carbonate and 2.1 g. ofcopper-bronze powder is heated in an oil bath at a bath temperature of220-230 C. for 24 hours. The cooled dark brown viscous mass is extractedwith 750 ml. of acetone and the solvent removed under reduced pressure.To the dark brown residue, 180 ml. of concentrated hydrochloric acid in515 ml. of ethanol is added. The mixture is refluxed for five hours andallowed to stand at room temperature over night. It is then poured into2.5 liters of cold water and made just alkaline with sodium hydroxide.Extraction with ether and removal of the dried solvent under reducedpressure gives a dark residue which is vacuum distilled to yield a paleyellow oil, 3-trifluoromethylmercaptodiphenyl amine, 115-119" C./ 0.3mm.

A mixture of 117.0 g. of 3-trifluoromethylmercaptodiphenyl amine, 25.0g. of sulfur and 1.8 g. of iodine is heated in an oil bath at 145-160 C.for one and one-half hours under a stream of nitrogen. The cooledreaction mass is dissolved in one liter of boiling benzene and treatedwith chromatographic alumina and charcoal. Concentration of the filtrategives a solid, Z-trifluoromethylmercaptophenothiazine, whichrecrystallizes trom carbon tetrachloride as yellow plates, M.P. 165-166C. A mixture of 29.9 g. of 2-trifluoromethylmercaptophenothiazine, 4.1g; of sodamide and 25.7 g. of N-carbethoxy-N'- (3chloropropyl)-piperazine is stirred and heated at reflux for eighthours. Working up the reaction mixture as in Example 1 yields 10-[3-(N-carbethoxypiperazinyl)-propyl] 2 trifluoromethylmercaptophenothiazinewhich is hydrolyzed by heating for minutes in an aqueous ethanolsolution containing slightly less than one equivalent of sodiumhydroxide.

A solution of 10.6 g. of 10-(3-piperazinyl-propyl)- 2trifluoromethylmercaptophenothiazine (prepared as above), 4.0 g. ofp-methylacetophenone, 2.0 g. of paraformaldehyde and 0.7 ml. ofconcentrated hydrochloric acid in 30 ml. of ethanol is stirred andrefluxed for four hours. Working up the reaction mixture as described inExample 1 yieldsl-(p-methylbenzoylethyl)-4-[3-(2-trifluoromethylmercapto-IO-phenothiazinyl)-propyl]-piperazine dihydrochloride.

Example 10 A mixture of 6.9 g. of 2-methylsulfonylphenothiazine, 1.0 g.of sodamide and 8.0 g. of 3-chloro-l-(l\-carbethoxy-2,5-diethylpiperazinyl)-propane (prepared from the reactionof 3-chloro-1-bromopropane with the N-carbethoxy derivative of2,5-diethylpiperazine) in 150 ml. of toluene is heated at reflux for 10hours. Cooling and working up as in Example 1 yields10-[3-(N-carbethoxy- 2,5diethylpiperazinyl)-propyl]-2-methylsulfonylphenothiazine. The lattercompound is hydrolyzed by refluxing for two hours an aqueous ethanolicsolution with 40% sodium hydroxide solution.

A solution of 4.6 g. of 2-methylsulfonyl-10-[3-(2,5- diethylpiperazinyl)propyl] phenothiazine (prepared as above) and 2.3 g. offl-bromopropiophenone in 50 ml. of dimethylformamide is heated at C. forfive hours. Working up the reaction mixture as in Example 2 yields1-(2-benzoylethyl) 4-[3 (2methylsulfonyl-lO-phenothiazinyl)-propyl]2,5-diethylpiperazine.

Example 11 A solution of 12.0 g. of chromic anhydride, 12.0 g. ofsulfuric acid and 40 ml. of water is mixed with 23.1 g. of3-nitro-4-chloropheny1 trifiuoromethyl sulfide and the resulting mixtureis stirred for 15 hours at -130 C. Steam distilling the reaction mixtureyields 3-nitro-4- chlorophenyltrifiuoromethyl sulfone.

A solution of 4.0 g. of sodium hydroxide pellets in 30 ml. of water isadded to 18.9 g. of Z-bromothiophenol dissolved in 250 ml. of ethanoland the resulting mixture added to a solution of 28.9 g. of3-nitro-4-chlorophenyl trifiuoromethyl sulfone in 100 ml. of ethanol.The suspension is refluxed for three hours. The solid present isfiltered from the hot reaction mixture and washed several times with hotethanol. The combined alcoholic filtrate is diluted with a small amountof water and cooled to yield 2'bromo-2-nitro-4-trifluoromethylsulfonyldiphenyl The solvent is thenremoved by distillation in vacuo and upon purification of the residue,2'-bromo-2-amino-4-trifiuoromethylsulfonyldiphenyl sulfide is obtained.

A suspension of 27.4 g. of2-bromo-2-amiuo-4-trifluoromethylsulfonyldiphenyl sulfide, 11.0 g. ofanhydrous potassium carbonate and 0.5 g. of copper-bronze powder in 300ml. of dimethylformamide is stirred and heated at reflux for 18 hours.The cooled reaction mixture is filtered and the filtrate diluted withwater. The solid which thusforms is vacuum sublimed at 0.05 mm.

195 C.) and recrystallized to give pure2-trifluoromethylsulfonylphenothiazzine.

A mixture of 3.3 g. of Z-trifluoromethylsulfonylphenothiazine, 0.4 g. ofsodium amide and 2.6 g. of N-carbethoxy-N-(3-chloropropyl)-piperazine in100 ml. of toluene is heated at reflux for eight hours. The cooledreaction mixture is worked up following Example 1 to give [3(N-carbethoxypiperazinyl)propyl]-2-trifluoromethylsulfonylphenothiazine.

A solution of 10.6 g. of 10-[3-(N-carbethoxypiperazinyl) propyl]-2-trifluoromethylsulfonylphenothiazine in 60 ml. of ethanol and 20 ml.of water containing 2 ml. of 40% sodium hydroxide solution is refluxedfor 90 minutes. Removing the solvent and treating as in Example 1 gives10-(3-piperazinylpropy1)-2-trifluoromethylsulfonylphenothiazine.

A solution of 22.8 g. of 10-(3-piperazinyl-propyl)-2-trifluoromethylsulfonylphenothiazine, 9.0 g. of p-methoxyacetophenone,3.2 g. of paraformaldehyde and 1.5 ml. of concentrated hydrochloric acidin 50 ml. of ethanol is stirred and heated at reflux for four hours.Working up the reaction mixture as outlined in Example 1 yieldsl-(p-methoxybenzoylethyl) 4[3-(2-trifluoromethylsulfonyl-lO-phenothiazinyl)-propyl]-piperazinedihydrochlotitle.

Example 12 A mixture of 10.5 g. of 2-cyanophenothiazine, 1.9 g. ofsodium amide and 12.1 g. of N-carbethoxy-N-(3-chloropropyl)-piperazinein 200 ml. of toluene is stirred and refluxed for eight hours. Workingup as in Example 1 yields10-[3-(N-carbethoxypiperaziny1)-propyl]-2-eyanophenothiazine. The lattercompound is hydrolyzed by refluxing an aqueous ethanol solution with 40%sodium hydroxide solution.

A solution of 7.0 g. of Z-cyano-10-(3-piperazinylpropyl)-phenothiazine(prepared as above) and 4.7 g. of fl-bromopropiophenone in ml. ofdimethyl-formamide is stirred and heated at C. for six hours. Working upthe reaction mixture as in Example 2 yields 1-(2- benzoylethyl) 4 [3 (2cyano 10 phenothiazinyl)- propyl] -pip erazine.

A solution of the free base in ethyl acetate is treated with an ethylacetate solution of maleic acid to give the dimaleate salt.

Reaction of the free base with sulfuric acid furnishes the sulfate salt.

What is claimed is:

1. 1 (2 benzoylethyl) 4 [3 (2 trifluoromethyl- 10-phe nothiazinyl)-propy1] -pip erazine.

2. 1 (2 benzoylethyl) 4 [3 (2 trifluoromethyl 1O phenotbiazinyl) propyl]piperazine dihydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS2,827,459 Horclois Mar. 18, 1958 2,874,155 Cusic Feb. 17, 1959 2,914,528Craig Nov. 24, 1959 2,928,767 Gulesich et al Mar. 15, 1960 FOREIGNPATENTS 203,708 Australia Oct. 20, 1955 780,193 Great Britain July 31,1957 OTHER REFERENCES Craig: J. Org. Chem, vol. 22, pp. 709-711 (June1957).

1. 1-(2-BENZOYLETHYL) -4-(3-(2-TRIFLUOROMETHYL10-PHENOTHIAZINYL)-PROPYL)-PIPERAZINE.